Benzoic acid derivatives and processes for the preparation thereof

ABSTRACT

Benzoic acid derivatives useful as intermediates for the preparation of drugs and agricultural chemicals, particularly compounds having herbicidal activity; and easy and economical processes for the preparation of the same. The processes are specifically those represented by reaction formula for the preparation of compounds represented by general formulae (1) and (6).

FIELD OF THE INVENTION

The present invention relates to benzoic acid derivatives useful asintermediates for the preparation of drugs and agricultural chemicals,particularly compounds having herbicidal activity, and to processes forthe preparation thereof.

BACKGROUND ART

A method (A) of obtaining benzoic acid derivatives by reactionsrepresented by the following reaction scheme,

between bicycloheptenone derivatives substituted with carboxylates andalcolates or the like is described in Tetrahedron, 42, 1741 (1986) andJ. Org. Chem., 26, 2066 (1961).

However, there are no reports on reactions of bicycloheptenonederivatives substituted with hetero rings.

Known methods of dehalogenation of aromatic halogenated compoundsinclude, for example, catalytic hydrogenolysis using palladium-carbon orRaney nickel as a catalyst, a method of using metal and metal salts suchas lithium or sodium, hydrogenolytic reduction with tin hydride,reduction with metal-hydrogen complex compounds such as lithium aluminumhydride, and electrolytic reduction, which are described in ShinJikkenkagakukouza, Vol. 14, Syntheses and Reactions of Organic Compounds[I] pages 22-30 (edited by the Chemical Society of Japan, published byMaruzen Co., Ltd.).

DISCLOSURE OF THE INVENTION

Substituted benzoic acid compounds, such as 4-alkylthiobenzoic acidderivatives, are important as intermediates for the preparation ofagricultural chemicals and drugs. It has been desired to develop easyand industrially advantageous processes for the preparation of the saidbenzoic acid derivatives.

The present invention is directed to

(a) a benzoic acid derivative represented by Formula (1)

 (wherein R¹ is hydrogen or C₁₋₄ alkyl,

R² is hydrogen or C₁₋₆ alkyl, and

Q is an optionally substituted, saturated or unsaturated, 5- or6-membered heterocyclic group containing 1 to 4 N, O or S atoms andcombining with the benzene ring via a carbon atom);

(b) a process for the preparation of a benzoic acid derivative of thesaid Formula (1), characterized by acting a base on a bicycloheptenonederivative of Formula (2)

 (wherein R¹ and Q are as defined above), in an appropriate solvent;

(c) a process for the preparation of a benzoic acid derivative of thesaid Formula (1), characterized by consisting of a stage of preparing abicycloheptenone derivative of the said Formula (2) by hydrolysis of abicycloheptene derivative of Formula (3)

 (wherein R¹ are as defined above, and X is chlorine or C₁₋₄ alkoxy andtwo X's may join to form a C₂₋₃ alkylenedioxy group optionallysubstituted with C₁₋₄ alkyl), and of acting a base and water or alcoholon a bicycloheptenone derivative of the said Formula (2) in anappropriate solvent;

(d) a process for the preparation of a bicycloheptene derivative of thesaid Formula (3), characterized by reacting a cyclopentadiene derivativeof Formula (4)

 (wherein X is as defined above) with an ethylene derivative substitutedwith a hetero ring, of Formula (5)

 (wherein R¹ and Q are defined above);

(e) a bicycloheptenone derivative of the said formula (2); and

(f) a process for the preparation of a benzoic acid derivative ofFormula (6)

 (wherein R¹, R² and Q are as defined above and R⁴ is C₁₋₆ alkyl),characterized by reacting a 4,5-dichlorobenzoic acid derivative of thesaid Formula (1), with a mercaptan of Formula R⁴SH (wherein R⁴ is asdefined above) and a base or with a salt of mercaptan of Formula R⁴SH(wherein R⁴ is as defined above)

In the definitions of the compounds of the said Formulae (1) and (2),which are the compounds of the present invention, the compounds ofFormula (3) of their precursors and the compounds of Formula (6),

R¹ is hydrogen, or C₁₋₄ alkyl such as methyl, ethyl, propyl, isopropyln-butyl isobutyl s-butyl or t-butyl;

a R² is hydrogen, or C₁₋₆ alkyl such as methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, s-butyl t-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl or isohexyl;

X is halogen such as chlorine, or C₁₋₄ alkoxy such as methoxy, ethoxy,propoxy, isopropoxy or butoxy;

Two X's may join to form a C₂₋₃ alkylenedioxy group, such asethylenedioxy or trimethylenedioxy;

Further, the said C₂₋₃ alkylenedioxy group may be substituted with C₁₋₄alkyl such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,s-butyl and t-butyl; and

Q is an optionally substituted, saturated or unsaturate 5- or 6-memberedheterocyclic group containing 1 to 4 N, O or S atoms and combining withthe benzene or bicycloheptane ring via a carbon atom.

Such hetero rings include, for example, 5-membered heterocyclic groupscontaining 1 to 4 N, O or S atoms, such as

2-furyl, 3-furyl,

2-thienyl, 3-thienyl,

2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl,2,3-dihydrofuran4-yl,2,3-dihydrofuran-5-yl, 2,5-dihydrofuran-2-yl,2,5-dihydrofuran-3-yl,

2,3-dihydrothiophen-2-yl, 2,3-dihydrothiophen-3-yl,2,3-dihydrothiophen-4-yl, 2,3-dihydrothiophen-5-yl,2,5-dihydrothiophen-2-yl, 2,5-dihydrothiophen-3-yl,

pyrrol-2-yl, pyrrol-3-yl,

imidazol-2-yl, imidazol-4-yl, imidazol-5-yl,

2-imidazolin-2-yl, 2-imidazolin-4-yl, 2-imidazolin-5-yl,

pyrazol-3-yl, pyrozol-4-yl, pyrazol-5-yl,

oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,

isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl.

1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl,

4-thiazolyl, 4-thiazolyl, 5-thiazolyl,

isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,

1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl,1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl,

1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,4-triazol-2-yl,1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, tetrazol-5-yl,

2-pyrrolin-1-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 2-pyrrolin4-yl,2-pyrrolin-5-yl,

2-oxazolin-2-yl, 2-oxazolin-4-yl, 2-oxazolin-5-yl, 3-oxazolin-2-yl,3-oxazolin-4-yl, 3-oxazolin-5-yl, 4-oxazolin-2-yl, 4-oxazolin-4-yl,4oxazolin-5-yl,

2-isoxazolin-3-yl, 2-isoxazolin-4-yl, 2-isoxazolin-5-yl,

3-isoxazolin-3-yl, 3-isoxazolin-4-yl, 3-isoxazolin-5-yl,

4-isoxazolin-3-yl, 4-isoxazolin-4-yl, 4-isoxazolin-5-yl,

2-thiazolin-2-yl, 4-thiazolin-4-yl, 4-thiazolin-5-yl,

2-isothiazolin-3-yl, 2-isothiazolin-4-yl, 2-isothiazolin-5-yl,

3-isothiazolin-3-yl, 3-isothiazolin-4-yl, 3-isothiazolin-5-yl,

4-isothiazolin-3-yl, 4-isothiazolin-4-yl, 4-isothiazolin-5-yl,

1-pyrazolin-3-yl, 1-pyrazolin-4-yl, 1-pyrazolin-5-yl,

2-pyrazolin-3-yl, 2-pyrazolin-4-yl, 2-pyrazolin-5-yl,

3-pyrazolin-3-yl, 3-pyrazolin-4-yl and 3-pyrazolin-5-yl; saturated5-membered heterocyclic groups containing 1 to 4 N, O or S atoms, suchas

2-pyrrolidinyl, 3-pyrrolidinyl,

2-tetrahydrofuranyl, 3-tetrahydrofuranyl,

2-tetrahydrothienyl, 3-tetrahydrothienyl,

2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl,

3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl,

2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl,

3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl,

2-imidazolidinyl, 4-imidazolidinyl,

1,2,4-oxadiazolidin-3-yl, 1,2,4-oxadiazolidin-5-yl,1,3,4-oxadiazolidin-2-yl,

1,2,4-thiadiazolidin-3-yl, 1,2,4-thiadiazolidin-5-yl,1,3,4-thiadiazolidin-2-yl,

1,3,4-triazolidin-2-yl,

1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl,

1,3-dithiolan-2-yl, 1,3-dithiolan-4-yl, and

1,3-oxathiolan-2-yl; and

6-membered heterocyclic groups containing 1 to 4 N, O or S atoms, suchas

2-pyridyl, 3-pyridyl, 4-pyridyl,

3-pyridazinyl, 4-pyridazinyl,

2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,

pyrazin-2-yl,

2H-pyran-3-yl, 2H-thiopyran-3-yl,

2-piperidinyl, 3-piperidinyl, 4-piperidinyl

2-piperadinyl,

2-morpholinyl, 3-morpholinyl,

5,6-dihydro-4H-1,3-thiazin-2-yl,

2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl,

2-tetrahydrothiopyranyl, 3-tetrahydrothiopyranyl and4-tetrahydrothiopyranyl.

These groups may have one or more, same or different, substituents atarbitrary positions of the hetero rings. Such substituents include, forexample, C₁₋₄ alkyl such as methyl, ethyl, propyl isopropyl, n-butyl,isobutyl, s-butyl and t-butyl, and C₁₋₄ haloalkyl such as chloromethyl,dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyland pentafluoroethyl.

Q is more preferably one of the following groups represented by Q-1 toQ-9.

In the above formulae, R³ is, for example, C₁₋₄ alkyl such as methyl,ethyl, propyl, isopropyl, n-butyl, isobutyl, s-butyl or t-butyl, or C₁₋₄haloalkyl such as chloromethyl, dichloromethyl, trichloromethyl,fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl,1,1-difluoroethyl, 2,2,2-trifluoroethyl or pentafluoroethyl, and n is 0or an integer of 1 or 2.

Further, in the said Formula (6), R⁴ is C₁₋₆ alkyl such as methyl,ethyl, propyl, isopropyl, n-butyl, isobutyl s-butyl, t-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl or isohexyl.

The compounds of the present invention, represented by the said Formulae(2) and (3), may have stereoisomers, depending on substituents atpositions 5 and 6. They are all covered by the present invention.

IMPLEMENTATION OF THE INVENTION

The compounds of the present invention may be produced by the followingprocesses:

(Process 1) Process for the Preparation of a 4,5-dichlorobenzoic AcidDerivative from a Bicycloheptenone Derivative

(wherein R¹, R² and Q are as defined above).

A bicycloheptenone derivative (2) of Formula (2) is reacted with a baseand water or alcohol in an appropriate solvent to give a compound ofFormula (1).

Bases used for this reaction include, for example, alkali metalalcolates such as sodium methylate, sodium ethylate and potassiumt-butoxide; alkali metal hydroxides such as sodium hydroxide andpotassium hydroxide; alkaline earth metal hydroxides such as calciumhydroxide; alkali metal carbonates such as sodium carbonate, potassiumcarbonate and sodium hydrogen carbonate; and alkaline earth metalcarbonates.

An amount of a base used is preferably 2 to 5 equivalents to 1 mole of abicycloheptenone derivative (2).

Solvents able to be used for the reaction include alcohols such asmethanol, ethanol, propanol, isopropanol, butanol and t-butanol; etherssuch as diethyl ether and tetrahydrofuran (THF); hydrocarbons such asbenzene and toluene; acetonitrile, dimethylformamide (DMF), water,toluene, benzene and the like, or mixtures of 2 or more of thesesolvents.

In the aforementioned reaction, it is particularly preferable to usealcoholic solvents, that is, alcohols, or mixed solvents of alcohol andother solvents such as water and alcohol or alcohol and ether.

In the above reaction, an ester (COOR²) having a portion correspondingto an alcohol (R²OH) used or the alkoxide portion of a metal alkoxide(MOR²) used can be obtained; for example, a methyl ester is obtainedwith the use of methyl alcohol and an ethyl ester from ethyl alcohol.

More preferred combinations of a base and a solvent include, forexample, sodium methoxide and methanol (or a mixed solvent of methanoland other solvents), sodium ethoxide and ethanol (or a mixed solvent ofethanol and other solvents), sodium hydroxide and alcohol (or a mixedsolvent of alcohol and other solvents), potassium hydroxide and alcohol(or a mixed solvent of alcohol and other solvents), and potassiumt-butoxide and butanol.

In the case of the use of mixed solvents or aqueous solvents, carboxylicacids (R²=H) can be obtained. Solvents used together with water arefavorably alcohols and ethers. As for bases, the aforementionedhydroxides or carbonates are preferably used.

In the case of the use of metal alkoxides, it is preferable to usecorresponding alcohols, as described above. It is of course possible touse other alcohols.

Preferred reaction temperatures are between −10° C. and the boilingpoint of solvents used.

(Process 2)

(wherein R¹, R², Q and X are as defined above.)

A bicycloheptenone derivative (2) can be obtained by hydrolysis of abicycloheptene derivative (3) with an acid such as hydrochloric acid orsulfuric acid.

That is, a compound (2) can be obtained by hydrolyzing a compound (3)without using a solvent or with a solvent including alcohols such asmethanol, ethanol and t-butanol, ethers such as diethyl ether andtetrahydrofuran (THF) or aromatic hydrocarbons such as benzene andtoluene, or a mixed solvent of two or more of these solvents, attemperature between −10° C. and the boiling point of solvents used.

After this, a target benzoic acid derivative can be prepared in the sameway as that described in Process 1 above.

(Process 3)

(wherein R¹, R², Q and X are as defined above.)

A Diels-Alder reaction of a cyclopentadiene derivative (4) and anethylene derivative substituted with a hetero ring (5) gives abicycloheptene derivative (3).

The Diels-Alder reaction can be carried out according to methodsdescribed, for example, in Tetrahedron, 42, 1741-1744 (1986) or J. Org.Chem., 26, 2066-2072 (1961).

In the above reaction, cyclopentadienes and ethylene derivatives arereacted while heating. A molar ratio of the ethylene derivatives used inthe reaction is 0.5 to 10 times in equivalent, preferably 1 to 3equivalents, to 1 mole of cyclopentadienes. The reaction is carried outat temperature between room temperature and 25° C., more preferablybetween 70° C. and 200° C.

Although this reaction is usually carried out without solvents, solventsmay be used. Examples of solvents used include aromatic hydrocarbonssuch as benzene, toluene, xylene, chlorobenzene and dichlorobenzene;alcohols such as ethanol, n-propyl alcohol, ethylene glycol,1,3-butanediol and ethylene glycol monomethyl ether; ethers such asdimethoxyethane, dioxane and diethylene glycol dimethyl ether, amidessuch as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrolidoneand N,N-dimethylimidazoline; hydrocarbons containing sulfur such asdimethylsulfoxide and sulfolane, and water.

The reaction proceeds more smoothly by adding a polymerization inhibitorsuch as hydroquinone in the presence of a base such as sodium hydrogencarbonate, potassium hydrogen carbonate, sodium carbonate or potassiumcarbonate.

After this, a target benzoic acid derivative can be produced in the sameway as that in Process 2.

A compound of Formula (5), a starting material, can be preparedaccording to methods described, for example, in the following papers:

Chim. Ind. (Milan), 52 (1), 56 (1977): Preparation of3-(1-propenyl)-1H-pyrrole;

Zh. Organ. Khim., 2, 417-423 (1966): Preparation of5-(1-propenyl)-isoxazole;

J. Org. Chem., 62, 3671-3677 (1997): Preparation of3(1-propenyl)-2-isoxazoline;

Heterocycles, 22 (11), 2475-2478 (1984): Preparation of4(1-propenyl)pyridine; and

Heterocycles, 29(1), 103-114 (1989): Preparation of5-(1-propenyl)-oxazole.

(Process 4)

(wherein R¹, R², R⁴ and Q are as defined above.)

In the process, a 4,5-dichlorobenzoic acid derivative of Formula (1) isreacted with an excessive amount of alkane thiol of Formula R⁴SH (R⁴ isas defined above) in an appropriate inert solvent in the presence of abase, to give a 4-alkylthiobenzoic acid derivative of Formula (6).

While doing so, the reaction proceeds more smoothly under theirradiation of light (of a specified wavelength). Various light sourcescan be used, including sunlight, fluorescent lights, mercury lamps, arclamps and incandescent lamps. It is preferable to carry out the reactionunder inert gas atmosphere, after the reaction system is sufficientlydegassed.

The reaction may sometimes proceed more smoothly by adding water of 0.1to 5 times in equivalent to the amount of 4,5-dichlorobenzoic acidderivative (1).

Particularly preferred solvents used for this reaction are amides, suchas dimethylformamide DMF), N,N-dimethylacetamide and N-methylpyrolidone.However, solvents used are not restricted to them.

Examples of bases used include hydroxides such as sodium hydroxide andpotassium hydroxide; carbonates such as sodium carbonate, sodiumhydrogen carbonate, potassium carbonate and potassium hydrogencarbonate; and metal alcolates such as sodium methylate, sodiumetheylate and potassium t-butoxide. In this case, a salt of alkanethiol, such as sodium or potassium salt of alkane thiol, prepared froman alkane thiol and a base beforehand, can be used for the reaction.

Amounts of base and alkane thiol used are preferably 2 to 20 equivalentsto that of 4,5-dichlorobenzoic acid derivative (1).

Benzoic acid derivatives of Formula (6) can be produced by isolation ofCompound (7) followed by reduction, as shown in the following reactionscheme:

To produce a compound of Formula (7), an equivalent of a compound ofFormula (1) is reacted with about 1 to 3 equivalents of an alkane thiolof Formula R⁴SH (R⁴ is as defined above) in an inert solvent in thepresence of an appropriate base.

In the reduction reaction from a compound of Formula (7) to a compoundof Formula (6), the same alkane thiol (R⁴SH) as that used in theprevious reaction can be used as a reducing agent. Further, otherreducing agents such as hydrogen sulfide and aromatic thiols can beemployed.

A compound of Formula (6) can be derived to a corresponding SO₂R⁴compound (8) by oxidation reaction of the SR⁴ group. This oxidationreaction may be carried out using an oxidizing agent including peroxidessuch as hydrogen peroxide, peracetic acid, perbenzoic acid andm-chloroperbenzoic acid, and hypochlorites such as sodium hypochloriteand potassium hypochlorite, in an inert solvent including water,alcohols such as methanol and ethanol organic acids such as acetic acid,and halogenated hydrocarbons such as dichloromethane, chloroform andcarbon tetrachloride. The reaction proceeds smoothly in the temperaturerange from 0° C. to the boiling point of the solvent used.

Further, a SO₂R⁴ compound (8) can be obtained by oxidation of a compoundof the said Formula (7) and then a reduction reaction fordechlorination.

(wherein R¹, R², R⁴ and Q are as defined above.)

A compound of Formula (9) can be produced by oxidation of a compound ofFormula (7). This oxidation reaction may be carried out using anoxidizing agent including peroxides such as hydrogen peroxide, peraceticacid, perbenzoic acid and m-chloroperbenzoic acid, and hypochloritessuch as sodium hypochlorite and potassium hypochlorite, in an inertsolvent including water, alcohols such as methanol and ethanol, organicacids such as acetic acid, and halogenated hydrocarbons such asdichloromethane, chloroform and carbon tetrachloride. The reactionproceeds smoothly in the temperature range from 0° C. to the boilingpoint of the solvent used.

The next dechlorination of a compound of Formula (9) is carried out bysuch a method as catalytic hydrogenolysis using Raney nickel as acatalyst, method of using metal and metal salts such as lithium andsodium hydrogenolytic reduction with tin hydride, reduction with ametal-hydrogen complex compound such as lithium aluminum hydride, orelectrolytic reduction, described in Shin Jikkenkagakukouza Vol. 14,Syntheses and Reactions of Organic Compounds [I] pages 22-30 (edited bythe Chemical Society of Japan, published by Maruzen Co., Ltd.).

The compounds of the present invention, intermediates and others can beobtained with usual post-treatments after the completion of thereactions.

The structures of the compounds of the present invention, intermediatesand others were determined by IR, NMR, MS and other means.

BEST FORM TO IMPLEMENT THE INVENTION

The present invention is described in more detail in reference toExamples and Reference Examples.

In Examples, of the compounds of the present invention, (1S, 4R, 5R, 6S)and (1R, 4S, 5S, 6R) isomers are represented as “trans”, and (1S, 4R,5R, 6R) and (1R, 4S, 5S, 6S) isomers as “cis”.

EXAMPLE 1 Preparation of ethyl4,5-dichloro-2-methyl-3-(3-methylisooxazol-5-yl)benzoate

0.11 g of6-methyl-5-(3-methylisoxazol-5-yl)-1,2,3,4-tetrachlorobicyclo[2.2.1]hept-2en-7-one(a mixture of trans:cis=1:1) was dissolved in 1 ml of ethanol, and 0.06g of sodium ethylate was added, while cooling with ice. The resultingsolution was stirred for an hour at room temperature. The reactionsolution was poured into 50 ml of ice-water, and extracted with 30 ml ofethyl acetate twice. The organic layer was washed with saturated saltwater and dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure. The obtained viscous liquid waspurified on silica gel column chromatography (elution withn-hexane/ethyl acetate) to give 0.024 g of the title compound as whitecrystals. Melting point 86-88° C.

EXAMPLE 2 Preparation of methyl4,5-dichloro-2-methyl-3-(3-methylisoxazol-5-yl)benzoate

To 0.99 g of6-methyl-cis-5-(3-methylisoxazol-5-yl)-7,7-dimethoxy-1,2,3,4-tetrachlorobicyclo[2.2]hept-2-enewas added 6.02 g of concentrated sulfuric acid, while cooling with ice.After returning to room temperature, the mixture was stirred for anhour. The resulting homogeneous solution was left undisturbed at roomtemperature for 15 hours. The reaction solution was poured into 20 ml ofice-water, and extracted with 20 ml of ethyl acetate twice. The organiclayer was washed with aqueous sodium bicarbonate twice and then withsaturated salt water, and dried over anhydrous magnesium sulfate. Themagnesium sulfate was removed and the solvent was concentrated underreduced pressure to give 0.79 g of a crude product of6-methyl-cis-5-(3-methylisoxazol-5-yl)-1,2,3,4-tetrachlorobicyclo[2.2.1]hept-2-en-7-oneas a yellow sticky substance.

0.94 g of the obtained crude6-methyl-cis-5-(3-methylisoxazol-5-yl)-1,2,3,4tetrachlorobicyclo[2.2.1.]hept-2-en-7-one was dissolved in 10 ml ofmethanol, and 1.44 g of a 28% methanol solution of sodium methylate wasdropped over 5 minutes, while cooling with ice. The resulting solutionwas stirred for 4 hours at room temperature, poured into 50 ml ofice-water, and extracted with 30 ml of ethyl acetate twice. The organiclayer was washed with saturated salt water and dried over anhydrousmagnesium sulfate. The solvent was concentrated under reduced pressure.The obtained viscous liquid was purified on silica gel columnchromatography (elution with n-hexane/ethyl acetate) to give 0.42 g ofthe title compound as white crystals. Melting point: 76-77° C.

EXAMPLE 3 Preparation of4,5-dichloro-2-methyl-5-(3-methylisoxazol-5-yl)benzoic acid

A solution of 156.9 g of6-methyl-cis-5-(3-methylisoxazol-5-yl1,2,3,4-tetrachlorobicyclo[2.2.1]hept-2-en-7-onein 1150 ml of THF was dropped into a solution of 92 g of sodiumhydroxide in 1150 ml of water at temperature between −3° C. and 0° C.over 1.5 hours. After the completion of the dropping, the cooling bathwas removed. The reaction solution was stirred for 1.5 hours, whilegradually rising the temperature to room temperature. After the reactionwas completed, 500 ml of toluene was added to the reaction solution, andthe aqueous layer was separated. Further, 500 ml of 1N aqueous solutionof sodium hydroxide was added to the organic layer, and the aqueouslayer was separated. The aqueous layers were combined, and 210 ml ofconcentrated hydrochloric acid was added to precipitate crystals. Thecrystals were separated by filtration, dissolved in 300 ml of ethylacetate, and dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure to give 95.0 g of the titlecompound as white crystals. Melting point: 212-213° C.

EXAMPLE 4 Preparation of methyl4,5-dichloro-2-methyl-3-(2-isoxazolin-3-yl)benzoate

To 1.0 g of6-methyl-cis-5-(2-isoxazolin-3-yl)-7,7-dimethoxy-1,2,3,4-tetrachlorobicyclo[2.2.1]hept-2-enewas added 6.3 g of concentrated sulfuric acid, while cooling with ice.After returning to room temperature, the mixture was stirred for anhour. The resulting homogeneous solution was left undisturbed at roomtemperature for 15 hours. The reaction solution was poured into 20 ml ofice-water and extracted with 20 ml of ethyl acetate twice. The organiclayer was washed with aqueous sodium bicarbonate twice and then withsaturated salt water, and dried over anhydrous magnesium sulfate. Themagnesium sulfate was removed and the solvent was concentrated underreduced pressure to give 0.94 g of a crude product of6-methyl-cis-5-(2-isoxazolin-3-yl)-1,2,3,4-tetrachlorobicyclo[2.2.1]hept-2-en-7-oneas a yellow sticky substance.

0.94 g of the obtained crude product was dissolved in 10 ml of methanol,and 1.5 g of a 28% methanol solution of sodium methylate was droppedover 5 minutes, while cooling with ice. The resulting solution wasstirred at room temperature for 2 hours. The reaction solution waspoured into 50 ml of ice-water, and extracted with 30 ml of ethylacetate twice. The organic layer was washed with saturated salt waterand dried over anhydrous magnesium sulfate. The solvent was concentratedunder reduced pressure. The obtained viscous liquid was purified onsilica gel column chromatography (with development solvents:n-hexane/ethyl acetate) to give 0.71 g of the title compound as whitecrystals. Melting point: 74-76° C.

The above procedure was repeated to produce ethyl4,5-dichloro-2-methyl-3-(2-isoxazolin-3-yl)benzoate. Melting point:96-97° C.

EXAMPLE 5 Preparation of4.5-dichloro-2-methyl-3-(2-isoxazolin-3-yl)benzoate

1.6 g of a crude product of6-methyl-cis-5-(2-isoxazolin-3-yl)-1,2,3,4-tetrachlorobicyclo[2.2.1]hept-2-en-7-one,obtained in the same manner as that in Example 4, was dissolved in 5 mlof tetrahydrofuran and 5 ml of water, and 14.6 g of 1N aqueous solutionof sodium hydroxide was dropped over 5 minutes, while cooling with ice.The resulting solution was stirred at room temperature for 2 hours. Thereaction solution was poured into 50 ml of ice-water, acidified in pHwith hydrochloric acid, and extracted with 30 ml of ethyl acetate twice.The organic layer was washed with saturated salt water, and dried overanhydrous magnesium sulfate. The solvent was concentrated under reducedpressure. The obtained crystals were washed with n-hexane to give 0.6 gof the title compound as white crystals. Melting point: 203-206° C.

EXAMPLE 6 Preparation of6-methyl-cis-5-(3-methylisoxazol-5-yl)-7,7-dimethoxy-1,2,3,4-tetrachlorobicyclo[2.2.1]hept-2-ene

2.15 g of 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopenta-1,3-diene, 0.81 gof sodium hydrogen carbonate, 1.00 g of1-(3-methylisoxazol-5-yl)-1-propene (an equivalent mixture of trans andcis isomers), 0.40 g of zinc iodide and 0.10 g of hydroquinone weremixed and heated with stirring at 150° C. for 8 hours. The reactionsolution was cooled and 100 ml of water was added. The resultingsolution was extracted with 200 ml of ethyl acetate. Insoluble matterpresent was removed by filtration. The organic layer was washed withsaturated salt water and dried over anhydrous magnesium sulfate. Thesolvent was concentrated under reduced pressure. n-Hexane was added tothe obtained crude product. The precipitated crystals were separated byfiltration to give 0.92 g of the title compound. Melting point: 100-101°C.

Further, the above filtrate was purified on silica gel columnchromatography (elution with benzene) to give 0.74 g of the tidecompound.

EXAMPLE 7 Preparation of6-methyl-cis-5-(3-methylisoxazol-5-yl)-7,7-dimethoxy-1,2,3,4-tetrachlorobicyclo[2.2.1]hept-2-ene

4.30 g of 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopenta-1,3-diene, 1.00 gof 1-(3-methylisoxazol-5-yl)-1-propene (an equivalent mixture of transand cis isomers) and 0.18 g of hydroquinone were added to 20 ml of1,3-butanediol. The resulting mixture was heated at reflux for 7 hours.The reaction solution was cooled, poured into ice-water, and extractedwith ethyl acetate. The organic layer was washed with saturated saltwater, and dried over anhydrous magnesium sulfate. The solvent wasconcentrated under reduced pressure. n-Hexane was added to the obtainedcrude product. The separated viscous oil was removed. The n-hexane layerwas concentrated under reduced pressure. The obtained crude product waspurified on silica gel column chromatography (elution with benzene) togive 1.41 g of the title compound as white crystals. Melting point:100-101° C.

EXAMPLE 8 Preparation of6-methyl-5-(3-methylisoxazol-5-yl)-7,7-dimethoxy-1,2,3,4-tetrachlorobicyclo[2.2.1]hept-2-ene

1.07 g of 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopenta-1,3-diene, 0.34 gof sodium hydrogen carbonate, 0.50g oftrans-1-(3-methylisoxazol-5-yl)-1-propene and 0.05 g of hydroquinonewere mixed and heated with stirring at 180° C. for 7 hours. The reactionsolution was cooled and ethyl acetate was added. Insoluble matter wasremoved by filtration. Then the solvent was concentrated under reducedpressure. The obtained crude product was purified on silica gel columnchromatography (elution with benzene) to give 0.70 g of the titlecompound as a mixture of isomers.

EXAMPLE 9 Preparation of6-methyl-cis-5-(3-methylisoxazol-5-yl)-7,7-dimethoxy-1,2,3,4-tetrachlorobicyclo[2.2.1]hept-2-ene

64.39 g of 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopenta-1,3-diene, 14.07g of sodium hydrogen carbonate, 20.00 g ofcis-1-(3-methylisoxazol-5-yl)-1-propene and 2.00 g of hydroquinone weremixed and heated with stirring at 120° C. for 6 hours. The reactionsolution was cooled and 500 ml of water was added. The resultingsolution was extracted with ethyl acetate three times. Insoluble matterpresent was removed by filtration. The organic layer was washed withsaturated salt water and dried over anhydrous magnesium sulfate.

The solvent was concentrated under reduced pressure. n-Hexane was addedto the obtained crude product. The precipitated crystals were separatedby filtration to give 45.81 g of the title compound. Melting point:100-101° C.

Further, the filtrate after the filtration of the crystals was purifiedon silica gel column chromatography (elution with benzene) to give 4.50g of the title compound.

¹H-NMR data of isomers (CDCl₃, δppm) cis isomer

0.83 (d, 3H), 2.30 (s, 3H), 3.08 (m, 1H), 3.58 (s, 3H), 3.66 (s, 3H),4.17 (d, 1H), 6.02 (s, 1H) trans isomer-1

1.40 (d, 3H), 2.30 (s, 3H), 2.37 (m, 1H), 3.58 (s, 3H), 3.62 (d, 1H),3.66 (s, 3H), 6.00 (s, 1H) trans isomer-2

1.09 (d, 3H), 2.34 (s, 3H), 2.84 (d, 1H), 3.07 (m, 1H), 3.50 (s, 3H),3.57 (s, 3H), 6.19 (s, 1H)

EXAMPLE 10 Preparation of6-methyl-cis-5-(2-isoxazolin-3-yl)-7,7-dimethoxy-1,2,3,4-tetrachlorobicyclo[2.2.1]hept-2-ene

2.14 g of 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopenta-1,3-diene, 0.46 gof sodium hydrogen carbonate and 0.6 g ofcis-1-(2-isoxazolin-3-yl)-1-propene were mixed and heated with stirringat 120° C. for 6 hours. The reaction solution was cooled to roomtemperature and ice-water was added. The resulting solution wasextracted with 200 ml of ethyl acetate. The organic layer was washedwith water and dried over anhydrous magnesium sulfate. The solvent wasconcentrated under reduced pressure. The obtained oily product waspurified on silica gel column chromatography (elution withn-hexane/ethyl acetate) to give 1.0 g of the title compound. Meltingpoint: 98-100° C.

EXAMPLE 11 Preparation of6-methyl-trans-5-(2-isoxazolin-3-yl)-7,7-dimethoxy-1,2,3,4-tetrachlorobicyclo[2.2.1]hept-2-ene

2.62 g of 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopenta-1,3-diene, 1.1 gof sodium hydrogen carbonate and 1.0 g oftrans-1-(2-isoxazolin-3-yl)-1-propene were mixed and heated withstirring at 200° C. for 20 hours. The reaction solution was cooled toroom temperature, poured into ice-water, and extracted with ethylacetate. The organic layer was washed with water and dried overanhydrous magnesium sulfate. The solvent was concentrated under reducedpressure. The obtained oily product was purified on silica gel columnchromatography (elution with n-hexane/ethyl acetate) to give 1.8 g ofthe title compound. n_(D) ^(19.9) 1.5087

EXAMPLE 12 Preparation of ethyl2-methyl-3-(3-methylisoxazol-5-yl)-4-methylthiobenzoate

0.50 g of ethyl 4,5-dichloro-2-methyl-3-(3-methylisoxazol-5-yl)benzoateand 4.40 g of potassium carbonate were added to 15 ml of DMF, and asolution of 1.53 g of methyl mercaptan dissolved in 5 ml of DMF wasdropped at room temperature. The resulting solution was further stirredfor 19.5 hours. Then, the reaction solution was poured into ice-waterand extracted with ethyl acetate. The organic layer was washed withwater and then with saturated salt water, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The obtained crudeproduct was purified on silica gel column chromatography to give 0.42 gof the title compound as white crystals. Melting point: 72-74° C.

EXAMPLE 13 Preparation of ethyl2-methyl-3-(3-methylisoxazol-5-yl)-4-methylthiobenzoate

4.48 g of ethyl 4,5-dichloro-2-methyl-3-(3-methylisoxazol-5-yl)benzoateand 3.00 g of potassium carbonate were added to 100 ml of DMF, and 2.1 gof methyl mercaptan gas was blown into the reaction system at roomtemperature. The resulting solution was further stirred at roomtemperature for 15 hours. The reaction solution was poured intoice-water and extracted with ethyl acetate. The organic layer was washedwith water and then with saturated salt water, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure to give 4.40g of ethyl5-chloro-2-methyl-3-(3-methylisoxazol-5-yl)-4-methylthiobenzoate aswhite crystals. Melting point: 79-82° C.

0.50 g of the obtained ethyl5-chloro-2-methyl-3-(3-methylisoxazol-5-yl)-4-methylthiobenzoate and1.06 g of potassium carbonate were added to 15 ml of DMF, and further asolution of 0.36 g of methyl mercaptan dissolved in 5 ml of DMF wasdropped at room temperature. The resulting solution was stirred at roomtemperature for 23 hours. The same procedure as that in Example 1 wasrepeated to give 0.29 g of the title compound as white crystals. 0.08 gof ethyl5-chloro-2-methyl-3-(3-methylisoxazol-5-yl)-4-methylthiobenzoate wasrecovered.

EXAMPLE 14 Preparation of methyl3-(2-isoxazolin-3-yl)-2-methyl-4-methylthiobenzoate

10 ml of degassed DMF was placed in a colorless, transparent glasscontainer, and 420 mg of methyl mercaptan was blown in to dissolve. Then600 mg of potassium carbonate and 500 mg of methyl4,5-dichloro-3-(2-isoxazolin-3-yl)-2-methylbenzoate were added one byone. The resulting solution was stirred with a Teflon magnetic stirrerat room temperature with light shielded under the nitrogen atmosphere.After stirring it for an hour, it was confirmed by NMR that methyl5-chloro-3-(2-isoxazolin-3-yl)-2-methyl-4-methylthiobenzoate was a majorproduct. Succeedingly, the reaction system was stirred at 40° C. for 2hours, while irradiating with white fluorescent light. The reactionsolution was poured into ice-water, and extracted with ether-chloroform(5:1) and then with ether. The organic layers were washed with water,dried over sodium sulfate, and concentrated under reduced pressure. Theobtained residue was purified on silica gel column chromatography(elution with n-hexane/ethyl acetate=95/5) to give 424 mg of the titlecompound as white crystals. Melting point: 109-111° C.

EXAMPLE 15 Preparation of t-butyl2-methyl-3-(3-methylisoxazol-5-yl)-4-methylthiobenzoate

27 mg of water was added to 10 ml of DMF, and 360 mg of methyl mercaptanwas blown into the resulting solution. Then the reaction system waspurged by nitrogen. To the resulting solution were added 518 mg ofpotassium carbonate and 513 mg of t-butyl4,5-dichloro-2-methyl-3-(3-methylisoxazol-5-yl)benzoate to stir at roomtemperature for 20 hours. The reaction solution was poured into 25 ml ofice-water and extracted with 25 ml of ether. The organic layer waswashed with water and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure. The obtained crude product waspurified on silica gel column chromatography (elution withn-hexane/ethyl acetate=95/5) to give 484 mg of the title compound with83% purity as a white solid. (The purity was determined by NMR spectra.)The product was again purified on silica gel column chromatography togive the title compound with melting point of 102-103° C. as whitecrystals.

EXAMPLE 16 Preparation of ethyl2-methyl-3-(2-isoxazolin-3-yl)-4-methylthiobenzoate

Into a 10-ml round-bottomed flask purged by nitrogen were placed 7.9 mgof water, 1.1 ml of DMF and a solution of 105 mg of methyl mercaptan in1.5 ml of DMF, and then 151 mg of potassium carbonate and 132 mg ofethyl 4,5-dichloro-3-(2-isoxazol-3-yl)-2-methylbenzoate were added. TheDMF used here was purged by nitrogen beforehand. The resulting mixturewas stirred with a magnetic stirrer at room temperature for 3 hours and45 minutes under the irradiation of 40W fluorescent light. The reactionsolution was poured into 20 ml of ice-water, and extracted with 20 ml ofdiethyl ether. The organic layer was washed with water, and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure. The obtained crude product was purified on silica gel columnchromatography (elution with n-hexane/ethyl acetate=95/5) to give 87.8mg of the title compound as white crystals. Melting point: 93˜94° C.

EXAMPLE 17 Preparation of ethyl4-ethylthio-2-methyl-3-(3-methylisoxazol-5-yl)benzoate

Into a 250-ml round-bottomed flask were placed 0.311 g of ethylmercaptan, 0.018 g of water and 6 ml of DMF, and then 0.346 g ofpotassium carbonate and 0.314 g of ethyl4,5-dichloro-2-methyl-3-(3-methylisoxazol-5-yl)benzoate were adder Theresulting mixture was stirred with a magnetic stirrer at roomtemperature for 6 hours under the irradiation of 40W fluorescent light.The reaction solution was poured into 25 ml of ice-water, and extractedwith 25 ml of diethyl ether. The organic layer was washed with water,and dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure. The obtained crude product was purified onsilica gel column chromatography (elution with n-hexane/ethylacetate=95/5) to give 0.132 g of the title compound as white crystals.Melting point: 39-40° C.

The above procedure was repeated to produce methyl4-methylthio-2-methyl-3-(3-methylisoxazol-5-yl)benzoate by reactingmethyl 4,5-dichloro-2-methyl-3-(3-methylisoxazol-5-yl)benzoate andmethyl mercaptan. Melting point: 94-95° C.

(REFERENCE EXAMPLES)

Examples of the preparation of the aforementioned 4-SO₂R⁴ compounds (8)are described in reference to Reference Examples.

Reference Example 1

Preparation of ethyl2-methyl-3-(3-methylisoxazol-5-yl)-4-methylsulfonylbenzoate

0.30 g of ethyl5-chloro-2-methyl-3-(3-methylisoxazol-5-yl)-4-methylsulfonylbenzoate wasdissolved in 20 ml of ethanol. After the reaction system was purged bynitrogen, 0.02 g of 5% palladium-carbon was added. The system was purgedby hydrogen. A rubber ball filled with hydrogen was attached and thesolution was stirred at room temperature for 3 hours. Thepalladium-carbon was removed from the reaction solution by filtration.The solvent was distilled off under reduced pressure to give 0.28 g ofthe title compound as white crystals. Melting point: 83-86° C.

Reference Example 2

Preparation of ethyl5-chloro-2-methyl-3-(3-methylisoxazol-5-yl)-4-methylsulfonylbenzoate

4.40 g ofethyl-5-chloro-2-methyl-3-(3-methylisoxazol-5-yl)-4-methylthiobenzoatewas dissolved in 50 ml of chloroform, and 12.70 g of 55%m-chloroperbenzoic acid was added at room temperature. The resultingsolution was stirred at room temperature for 19 hours. Precipitatedcrystals were separated from the reaction solution by filtration. Thefiltrate was washed with 80 ml of a 4% aqueous solution of sodiumhydroxide. The organic layer was dried over anhydrous magnesium sulfate.The solvent was distilled off under reduced pressure to give 4.49 g ofthe title compound as white crystals. Melting point: 126-129° C.

Representative examples of the compounds of Formulae (1) and (2) of thepresent invention, including those in the above examples, are shown inTables 1 and 2. The abbreviations of Q's in the tables have thefollowing meanings:

Q1: isoxazol-5-yl, Q2: 3-methylisoxazol-5-yl, Q3: isoxazol-3-yl, Q4:2-isoxazolin-3-yl, Q5: oxazol-2-yl, Q6: oxazol-4-yl, Q7: oxazol-5-yl,Q8: thiazol-2-yl, Q9: thiazol-4-yl, Q10: thiazol-5-yl, Q11:pyrazol-3-yl, Q12: 1-methyl-pyrazol-3-yl, Q13: 2-pyridyl: Q14:3-pyridyl, Q15: 4-pyridyl, Q16: pyrimidin-2-yl, Q17: pyrimidin-4-yl,Q18: pyrimidin-5-yl, Q19: 1,3-dioxoran-2-yl, and Q20: 1,3-dioxan-2-yl

TABLE 1 (1)

Compound No. Q Table 1-1 R¹: CH₃ R²: H 1-1 Q1 1-2 Q2 1-3 Q3 1-4 Q4 1-5Q5 1-6 Q6 1-7 Q7 1-8 Q8 1-9 Q9 1-10 Q10 1-11 Q11 1-12 Q12 1-13 Q13 1-14Q14 1-15 Q15 1-16 Q16 1-17 Q17 1-18 Q18 1-19 Q19 1-20 Q20 Table 1-2 R¹:CH₃ R²: CH₃ 1-21 Q1 1-22 Q2 1-23 Q3 1-24 Q4 1-25 Q5 1-26 Q6 1-27 Q7 1-28Q8 1-29 Q9 1-30 Q10 1-31 Q11 1-32 Q12 1-33 Q13 1-34 Q14 1-35 Q15 1-36Q16 1-37 Q17 1-38 Q18 1-39 Q19 1-40 Q20 Table 1-3 R¹: CH₃ R²: C₂H₅ 1-41Q1 1-42 Q2 1-43 Q3 1-44 Q4 1-45 Q5 1-46 Q6 1-47 Q7 1-48 Q8 1-49 Q9 1-50Q10 1-51 Q11 1-52 Q12 1-53 Q13 1-54 Q14 1-55 Q15 1-56 Q16 1-57 Q17 1-58Q18 1-59 Q19 1-60 Q20 Table 1-4 R¹: CH₃ R²: n-C₃H₇ 1-61 Q1 1-62 Q2 1-63Q3 1-64 Q4 1-65 Q5 1-66 Q6 1-67 Q7 1-68 Q8 1-69 Q9 1-70 Q10 1-71 Q111-72 Q12 1-73 Q13 1-74 Q14 1-75 Q15 1-76 Q16 1-77 Q17 1-78 Q18 1-79 Q191-80 Q20 Table 1-5 R¹: CH₃ R²: i-C₃H₇ 1-81 Q1 1-82 Q2 1-83 Q3 1-84 Q41-85 Q5 1-86 Q6 1-87 Q7 1-88 Q8 1-89 Q9 1-90 Q10 1-91 Q11 1-92 Q12 1-93Q13 1-94 Q14 1-95 Q15 1-96 Q16 1-97 Q17 1-98 Q18 1-99 Q19 1-100 Q20Table 1-6 R¹: CH₃ R²: n-C₄H₉ 1-101 Q1 1-102 Q2 1-103 Q3 1-104 Q4 1-105Q5 1-106 Q6 1-107 Q7 1-108 Q8 1-109 Q9 1-110 Q10 1-111 Q11 1-112 Q121-113 Q13 1-114 Q14 1-115 Q15 1-116 Q16 1-117 Q17 1-118 Q18 1-119 Q191-120 Q20 Table 1-7 R¹: CH₃ R²: n-C₄H₉ ^(a) 1-121 Q1 1-122 Q2 1-123 Q31-124 Q4 1-125 Q5 1-126 Q6 1-127 Q7 1-128 Q8 1-129 Q9 1-130 Q10 1-131Q11 1-132 Q12 1-133 Q13 1-134 Q14 1-135 Q15 1-136 Q16 1-137 Q17 1-138Q18 1-139 Q19 1-140 Q20 Table 1-8 R¹: CH₃ R²: t-C₄H₉ 1-141 Q1 1-142 Q21-143 Q3 1-144 Q4 1-145 Q5 1-146 Q6 1-147 Q7 1-148 Q8 1-149 Q9 1-150 Q101-151 Q11 1-152 Q12 1-153 Q13 1-154 Q14 1-155 Q15 1-156 Q16 1-157 Q171-158 Q18 1-159 Q19 1-160 Q20 Table 1-9 R¹: CH₃ R²: i-C₅H₁₁ 1-161 Q11-162 Q2 1-163 Q3 1-164 Q4 1-165 Q5 1-166 Q6 1-167 Q7 1-168 Q8 1-169 Q91-170 Q10 1-171 Q11 1-172 Q12 1-173 Q13 1-174 Q14 1-175 Q15 1-176 Q161-177 Q17 1-178 Q18 1-179 Q19 1-180 Q20 Table 1-10 R¹: CH₃ R²: t-C₅H₁₁1-181 Q1 1-182 Q2 1-183 Q3 1-184 Q4 1-185 Q5 1-186 Q6 1-187 Q7 1-188 Q81-189 Q9 1-190 Q10 1-191 Q11 1-192 Q12 1-193 Q13 1-194 Q14 1-195 Q151-196 Q16 1-197 Q17 1-198 Q18 1-199 Q19 1-200 Q20 Table 1-11 R¹: C₂H₅R²: H 1-201 Q1 1-202 Q2 1-203 Q3 1-204 Q4 1-205 Q5 1-206 Q6 1-207 Q71-208 Q8 1-209 Q9 1-210 Q10 1-211 Q11 1-212 Q12 1-213 Q13 1-214 Q141-215 Q15 1-216 Q16 1-217 Q17 1-218 Q18 1-219 Q19 1-220 Q20 Table 1-12R¹: C₂H₅ R²: CH₃ 1-221 Q1 1-222 Q2 1-223 Q3 1-224 Q4 1-225 Q5 1-226 Q61-227 Q7 1-228 Q8 1-229 Q9 1-230 Q10 1-231 Q11 1-232 Q12 1-233 Q13 1-234Q14 1-235 Q15 1-236 Q16 1-237 Q17 1-238 Q18 1-239 Q19 1-240 Q20 Table1-13 R¹: C₂H₅ R²: C₂H₅ 1-241 Q1 1-242 Q2 1-243 Q3 1-244 Q4 1-245 Q51-246 Q6 1-247 Q7 1-248 Q8 1-249 Q9 1-250 Q10 1-251 Q11 1-252 Q12 1-253Q13 1-254 Q14 1-255 Q15 1-256 Q16 1-257 Q17 1-258 Q18 1-259 Q19 1-260Q20 Table 1-14 R¹: C₂H₅ R²: n-C₃H₇ 1-261 Q1 1-262 Q2 1-263 Q3 1-264 Q41-265 Q5 1-266 Q6 1-267 Q7 1-268 Q8 1-269 Q9 1-270 Q10 1-271 Q11 1-272Q12 1-273 Q13 1-274 Q14 1-275 Q15 1-276 Q16 1-277 Q17 1-278 Q18 1-279Q19 1-280 Q20 Table 1-15 R¹: C₂H₅ R²: i-C₃H₇ 1-281 Q1 1-282 Q2 1-283 Q31-284 Q4 1-285 Q5 1-286 Q6 1-287 Q7 1-288 Q8 1-289 Q9 1-290 Q10 1-291Q11 1-292 Q12 1-293 Q13 1-294 Q14 1-295 Q15 1-296 Q16 1-297 Q17 1-298Q18 1-299 Q19 1-300 Q20 Table 1-16 R¹: C₂H₅ R²: n-C₄H₉ 1-301 Q1 1-302 Q21-303 Q3 1-304 Q4 1-305 Q5 1-306 Q6 1-307 Q7 1-308 Q8 1-309 Q9 1-310 Q101-311 Q11 1-312 Q12 1-313 Q13 1-314 Q14 1-315 Q15 1-316 Q16 1-317 Q171-318 Q18 1-319 Q19 1-320 Q20 Table 1-17 R¹: C₂H₅ R²: s-C₄H₉ 1-321 Q11-322 Q2 1-323 Q3 1-324 Q4 1-325 Q5 1-326 Q6 1-327 Q7 1-328 Q8 1-329 Q91-330 Q10 1-331 Q11 1-332 Q12 1-333 Q13 1-334 Q14 1-335 Q15 1-336 Q161-337 Q17 1-338 Q18 1-339 Q19 1-340 Q20 Table 1-18 R¹: C₂H₅ R²: t-C₄H₉1-341 Q1 1-342 Q2 1-343 Q3 1-344 Q4 1-345 Q5 1-346 Q6 1-347 Q7 1-348 Q81-349 Q9 1-350 Q10 1-351 Q11 1-352 Q12 1-353 Q13 1-354 Q14 1-355 Q151-356 Q16 1-357 Q17 1-358 Q18 1-359 Q19 1-360 Q20 Table 1-19 R¹: C₂H₅R²: i-C₅H₁₁ 1-361 Q1 1-362 Q2 1-363 Q3 1-364 Q4 1-365 Q5 1-366 Q6 1-367Q7 1-368 Q8 1-369 Q9 1-370 Q10 1-371 Q11 1-372 Q12 1-373 Q13 1-374 Q141-375 Q15 1-376 Q16 1-377 Q17 1-378 Q18 1-379 Q19 1-380 Q20 Table 1-20R¹: C₂H₅ R²: t-C₅H₁₁ 1-381 Q1 1-382 Q2 1-383 Q3 1-384 Q4 1-385 Q5 1-386Q6 1-387 Q7 1-388 Q8 1-389 Q9 1-390 Q10 1-391 Q11 1-392 Q12 1-393 Q131-394 Q14 1-395 Q15 1-396 Q16 1-397 Q17 1-398 Q18 1-399 Q19 1-400 Q20

TABLE 2 (2)

Compound No. Q Table 2-1 R¹: CH₃ 2-1 Q1 2-2 Q2 2-3 Q3 2-4 Q4 2-5 Q5 2-6Q6 2-7 Q7 2-8 Q8 2-9 Q9 2-10 Q10 2-11 Q11 2-12 Q12 2-13 Q13 2-14 Q142-15 Q15 2-16 Q16 2-17 Q17 2-18 Q18 2-19 Q19 2-20 Q20 Table 2-2 R¹: C₂H₅2-21 Q1 2-22 Q2 2-23 Q3 2-24 Q4 2-25 Q5 2-26 Q6 2-27 Q7 2-28 Q8 2-29 Q92-30 Q10 2-31 Q11 2-32 Q12 2-33 Q13 2-34 Q14 2-35 Q15 2-36 Q16 2-37 Q172-38 Q18 2-39 Q19 2-40 Q20

TABLE 3 (6)

Table 3-1 Compounds 3-1 to 3-400, where R⁴ is CH₃, that are derived fromCompounds Nos. from 1-1 to 1-400 in Table 1. Table 3-2 Compounds 3-401to 3-800, where R⁴ is C₂H₅, that are derived from Compounds Nos. from1-1 to 1-400 in Table 1. Table 3-3 Compounds 3-801 to 3-1200, where R⁴is i-C₃H₇, that are derived from Compounds Nos. from 1-1 to 1-400 inTable 1. Table 3-4 Compounds 3-1201 to 3-1600, where R⁴ is t-C₄H₉, thatare derived from Compounds Nos. from 1-1 to 1-400 in Table 1.

Applicability in Industry

As described above, according to the present invention, benzoic acidderivatives useful as intermediates for the preparation of agriculturalchemicals and drugs, particularly compounds having herbicidal activity,can be produced simply, easily and industrially advantageously in ashort process, using inexpensive cyclopentadiene derivatives andethylene derivatives substituted with hetero rings as startingmaterials.

For example, reactions of compounds of Formula (6), which are producedaccording to the present invention, with 3-hydroxypyrazoles giveherbicides disclosed in WO 96/26206, WO 97/41118 and others.

What is claimed is:
 1. A process for the preparation of a substitutedbenzoic acid of Formula (1)

wherein R¹is hydrogen or C₁₋₄ alkyl, R² is hydrogen or C₁₋₆ alkyl, and Qis an optionally substituted, saturated or unsaturated, 5- or 6-memberedheterocyclic group wherein said heterocyclic group is selected from thegroup consisting of: a) a five member heterocyclic ring having at leastone heteroatom which is selected from the group consisting of N, O, orS, and where the heterocyclic group is linked to the benzene ring via acarbon atom; or b) a six member heterocyclic ring having at least oneheteroatom which is selected from the group consisting of N, O, or S,and where the heterocyclic group is linked to the benzene ring via acarbon atom; which comprises reacting a substituted bicycloheptenone ofFormula (2)

wherein R¹ is as defined above and Q

is an optionally substituted, saturated or unsaturated, 5- or 6-memberedheterocyclic group wherein said heterocyclic group is selected from thegroup consisting of: a) a five member heterocyclic ring having at leastone heteroatom which is selected from the group consisting of N, O, orS, and where the heterocyclic group is linked to the benzene ring via acarbon atom; or b) a six member heterocyclic ring having at least oneheteroatom which is selected from the group consisting of N, O, or S,and where the heterocyclic group is linked to the benzene ring via acarbon atom; with a base and water or alcohol of Formula R₂OH, whereinR₂ is hydrogen or C₁₋₆ alkyl, in an appropriate solvent, and wherein thebase is an alkali metal alkoxide, all alkali metal hydroxide or analkaline earth metal hydroxide, the alcohol is methanol, ethanol,propanol, isopropanol, butanol or t-butanol, and the solvent ismethanol, ethanol, propanol, isopropanol, butanol or t-butanol, or THF.2. A process for the preparation of a substituted benzoic acid ofFormula (1)

wherein R¹ is hydrogen or C₁₋₄ alkyl, R² is hydrogen or C₁₋₆ alkyl, andQ is selected from the group consisting of Q-1, Q-2, Q-3, Q-4, Q-5, Q-6,Q-7, Q-8 and Q-9

wherein R³ is C₁₋₄ alkyl or C₁₋₄ haloalkyl, and n is 0 or an integer of1 or 2, which comprises having a stage for the preparation of asubstituted bicycloheptenone of Formula (2)

wherein R¹ and Q are as defined above by hydrolysis of a substitutedbicycloheptene of Formula (3)

wherein R¹ and Q are as defined above, and X is chlorine or C₁₋₄ alkoxy;and the two X's may join together to form a C₂₋₃ alkylenedioxy groupoptionally substituted with C₁₋₄ alkyl, and a stage of reacting thesubstituted bicycloheptenone of the above Formula (2) with a base andwater or alcohol in an appropriate solvent, and wherein the base is analkali metal alkoxide, an alkali metal hydroxide or an alkaline earthmetal hydroxide, the alcohol is methanol, ethanol, propanol,isopropanol, butanol or t-butanol, and the solvent is methanol, ethanol,propanol, isopropanol, butanol or t-butanol, or THF.
 3. A process forthe preparation of a substituted benzoic acid of the above Formula (1)according to claim 1, in which the base is one or more compoundsselected from the group consisting of alkali metal alkoxides, alkalimetal hydroxides and alkaline earth metal hydroxides.
 4. A processaccording to claim 1, in which the solvent is an alcohol or a solventcontaining an alcohol.
 5. A process according to claim 2, in which thehetero ring represented by Q is a group selected from the followinggroup consisting of Q-1, Q-2, Q-3, Q-4, Q-5, Q-6, Q-7, Q-8 and Q-9

wherein R³ is C₁₋₄ alkyl or C₁₋₄ haloalkyl, and n is 0 or an integer of1 or 2.